Mast cells play a pivotal role in the pathogenesis of asthma and other allergic diseases. These reactions are generally initiated by antigen-dependent aggregation of the high affinity IgE receptor (Fc-epsilon-RI) expressed on the cell surface and subsequent release of pro-inflammatory mediators (e.g. histamine, prostanoids, proteases and cytokines). Although mast cell activation has traditionally been considered an antigen-dependent response mediated via the Fc{epsilon}RI, there is an increasing appreciation that other receptors (and other stimuli) may profoundly influence antigen-mediated degranulation. Furthermore, activating polymorphisms / mutations in, and alternatively spliced forms of receptors and/or signaling proteins may further modulate these responses. Such polymorphisms associated with disease states, for example mastocytosis may be manifested by exacerbated mast cell-dependent physiology. We wish therefore to explore how polymorphisms or alternatively spliced variants of receptors or signaling proteins may produce a hyperactive phenotype. Furhtermore we wish to identify disease states/clinical populations where hyper-responsive and low-responsive mast cells exist and identify signaling defects. Finally, we wish to explore potential approaches for inhibiting these responses.